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Meningitis, From Practitioner to Prescriber
Eugénie d’Alessandro
To cite this version:
Eugénie d’Alessandro. Meningitis, From Practitioner to Prescriber. Medical Innovations in Humani- tarian Situations The Work of Médecins Sans Frontières, 2009. �hal-01419384�
Chapter 6
Meningitis
From Practitioner to Prescriber
Eugénie d'Alessandro
eningococcal cerebrospinal meningitis is caused by a gram-
ne gative dipl ococcu s, N eis s eria meningitidi.s, also known as the meningococcus. Although meningococci are present throughout the world, causing sporadic cases and small epidemics, rnenin- gococcal disease is a different entity in semi-arid sub-Saharan
Aliica, where devastatine and unpredictable epidemics ()ccur.
This phenomenonwas first described in the 1960s by Dr. Lapeys- sonnie, a French Ar-y general in the medical services. Covering
a "band of terrain from the Atlantic to the Red Sea," the menin- gitis belt is an endemic-epidemic region. The epidemic risk is particularly high during the dry season. The severe conse- quences of these outbreaks in terms of morbidity and mortality make the disease a public health priority.
Lapeyssonnie refined the first single-dose treatment for meningococcal meningitis epidemics in the early 1960s. His works on the meninsococcus and its sensitivity t<-l antibiotic treatment created the hope that "the discovery of long-acting sulphamides may permit the reduction of medical inter-vention
to a single injection" (Lapeyssonnie, Momenteau, l96l;
Lapeyssonnie, Chabbert, Bonnardot, et al., 1961; Lapeys-
sonnie, Bonnardot, Louis, et al., 196l). In practice, it was
indeed difficult to give oral antibiotics three times a day to thousands of patients, some of them in comas, and spread over potentially large distances. This is why the development of a
long-acting intramuscular sulphamide, Sultirene, was a signif'-
icant step forward in treatment-due to its efficacy and ease of
use (Chippaux, 2001).
Sadly, the use «rl'this drug was quickly compr<>mised. Fewer
than ten years after its development, the first resistances appeared. By the beginning of the 1970s the sulphamides were
n«r longer sulliciently ellicacious, and classical seven- to ten-day treatments were difficult to administer in practice.
Michel R.y, back in France after a long spell in West
Afiica, where he had been in charqe «r[ the Inlêctious Diseases
department at Dakar Hospital, became involved in the research and development of short treatments for meningococcal menin- gitis. Inspired by Yves Chabbert at the Pasteur Institute (wh<r collaborated with Lapeyssonnie on long-acting sulphamides) and Jacques Acar, Rey launched a new single-dose treatment-oily chloramphenicol by intramuscular injection. Once the dosage
form was perfected, Rey and his team tested the treatment in several West African countries. Encouraging initial results were obtained in Dakar and Ouagaclougou (Rey et al., 1975). The study was completed by looking at 74 consecutive rneningitis
cases in Bobo-Dioulasso, treated by single injection of oily chlor- amphenicol. The results obtained in 1976 led the authors to propose chloramphenicol in oily suspension as an alternative to long-acting sulphamides in epidemics of cerebrospinal menin- gitis epidemics, and also as initial treatment for endemic and sporadic cases in rural African settings (Rey et al., 1976).
The efficacy of oral and intravenous chloramphenicol in the treatment of meningococcal meningitis had already been studied (Girgis et al., 1972; Whittle et al., 1973). The devel- opment of a long-acting intramuscular injection dosage form, however, allowed single-dose treatments. Following the results of this study, oily chloramphenicol was registered in France and produced by Roussel Laboratories.
Epicentre's Contribution to the Prescription of Oily Chloramphenicol and Ceftriaxone in Africa
Th. first major epidemic outbreak occurred in countries that
I u.. part of the so-called "meningitis belt" between 1987
and 1989. Sudan was particularly affected in 1988, followed by Ethiopia in l9ti9, reportinS; thirty-tw«r thousand and firrty- one thousand cases respectively (WHO, 1998). MSF opened a
mission in Sudan in 1988 and proposed oily chloramphenicol
for curative care of meningitis cases. The treatment protocol
was refused by Sudanese authorities as it did not correspond to national guidelines. MSF teams were thus forced to use ampi-
cillin injections over several days. A doctor from the mission explained that "half the patients left before finishing treatment.
It was.just impossible. 'fhe teams were soins out «r['their minds."
Medical practice and research in English-speaking coun-
tries evolved more quickly towards evidence-based medicine than in French-speaking countries. Tieatments and therapeutic protocols were studied according to international biomedical criteria and communicated thr«rugh publication in reputed
medical journals.
The single-dose oily chloramphenicol protocol was unheard
of in the {brmer British colonies at the time, despite being
in everyday use in French-speaking countries. Clinical trials carried out on the m«rlecule did not provide su[Iicient pro<>l'as
far as criteria in English-speaking countries were concerned. As far as we know, only four studies can be found in medical liter- ature before 1988, rwo of which were performed by Rey's team
in Saliou, in Senegal, and Ouedraogo, in Burkina Faso (1975, 1976), and published in French .journals. The other two were written by one English-speaking group (Wali et a1., 1979; Puddi- combe, Wali, Greenwood, 1984). Results were comparable: (l)
oily chloramphenicol seemed just as efficacious as longer, clas- sical treatments; (2) the single- or two-injection protocols were
significantly advantageous in resource-limited countries; (3) the low cost of treatment also made it more affordable in these
countries; (4) theoretical chloramphenicol toxicity appears negligible when compared with the morbidity and mortality of
meningococcal disease, particularly during epidemics. In short, this protocol appeared to be a promising firstJine treatment option in developing countries. None of these studies provided
"scientific approval" according to the standards in English- speaking countries, however. In all four studies, the numbers of patients studied were too low to provide statistically significant results, and only two were published in English,
MSF senior staff members were quickly convinced of the need for progress. They knew frorn their own experience that chloramphenicol was easier to use and efficacious. According to field doctors, this drug needed to be available for use in all meningococcal meningitis epidemics, including in East Africa.
The experience in Sudan demonstrated the need to perform an efficacy study according to international scientific norms.
The study protocol, written by an Epicentre epiderniologist,
was applied in two referral hospitals in Niamey and Bamako, in collaboration with Nigerien and Malian health authorities. An unblinded, randorn controlled trial of 515 patients compared the clinical and biological efficacy of two injections of oily chlor- amphenicol with the previous standard, which involved eight days of intravenous ampicillin.
Results showed comparable efficacy for the two treatments.
Given feasibility and cost criteria, the authors recommended the use of oily chloramphenicol as first-line treatment for bacterial meningitides in peripheral health structures in the Sudan-Sahel region. They also added that better chloramphenicol pharma- cokinetics studies were required to optimize treatment efficacy,
and, furthermore, that high mortality rates should motivate
further research for new, better, simple-to-use treatments such as ceftriaxone (Varaine, 1990).
The study was published in The Lan,cct in l99l (Pécoul,
Varaine, Keita, et al., 1991). These results scientifically validated the protocol and led to its worldwide transmission. Oily chlor- amphenicol use quickly became widespread in former British colonies lbllowing the publication o['this article (it was used in
l99l in Uganda, for example), and became the rule, as shown by national protocols in the Sudan-Sahel region from this time on.
In terms of international health policy, the World Health Organization flÂrHO) prt oily chloramphenicol on its essential drugs list, then subsequently recommended it in its first guide on controlling meningitis epidemics (WHO, 1995). It became
the recommended firstline treatment a few years later, in 1997, after the creation of the International Coordinating Group on Vaccine Provision lor Epidemic Meningitis Control (IC()), and still is today.
The drug is not fully accepted by some scientists and officials, however. Its toxicity in oral and intravenous use has been criti- cized, and the drugwas pulled from the European market after a
number of cases of bone marrow aplasia in richer countries. This led the original manufacturer, Roussel, to halt production. The International Dispensary Association (IDA) started pr<>duction after calls from MSF, but transferred production to an Indian pharmacological laboratory following technical production difficulties. This company is still the only oily chloramphenicol manufacturer in the world.
Some countries in the meningitis belt have categorically refused to use the drug, despite WHO recommendations,
because itwas seen as "a drug lbr poor countries."'fhere is o{ten confusion with respect to the benefits of this particular dosage
form and the use of the molecule in general. Over and above occasional refusals to use the drug, lack of knowledge also leads to doubts about its inclusion on the WHO essential drugs list.
Finally, an alternative exists: the third-generation cepha-
losporin ceftriaxone. During the 1990s, this drug was too expensive for use in resource-limited countries, particularly
in such large-scale public health interventions as menineitis epidemics.
MSF's involvement in ceftriaxone use began early, through a
randomized double-blincl trial in 1991 comparing the ellicacy of two injections of either oily chloramphenicol or ceftriaxone in the treatment of bacterial menineitis. The study was carried out in Niamey and Bamako bem,een lggl and 1995, and the study population included children of two to thirty-five months of age, suffering from purulent bacterial meningitis (all germs).
The results suggested that two injections of ceftriaxone were more efficacious in reducing mortality than two doses o[ oily chloramphenicol. The study authors publicly requested the immediate availability of cheaper generic ceftriaxone for use in r-esource-limited countries (Varaine et al., 1997). This position was restated at international confèrences and expert working groups, such as the Eighth Infectious Diseases Conference in Boston in 1998 (Varaine, Keita, Kaninda, et al., 1998).
'fhe signilicance o['the study results was somewhat limited, however. The study did not question the use of oily chloram- phenicol, nor did it examine efficacy during epidemics. The study was not carried out during epidemic periods, and only a
third of cases were meningococcal.
In 2002, facing increasing difficulties in the supply of oily chloramphenicol, and with the price of ceftriaxone progressive reduced, MSF and Epicentre decided to proceedwith an equiva- lence study comparing oily chloramphenicol and ceftriaxone.
The way this study was set up in the field is a good example of
MSF's specific potential. The aim was to recruit enough patients during an epidemic,' which, according to a senior Epicentre staff member, involved "being in the right place at the right time." The four selected countries for the study were Chad,
Mali, Nigeç and Burkina Faso. Preliminary negotiations to obtain agreements from the health authorities were successful
except in Burkina Faso. An epidemic then began in Burkina
Faso at the start of'winter 2003.'fhe MSF and Epicentre team immediately le{t lbr the site, but authorizations were slow tr-r arrive. Senior MSF' stall in I'aris then asked their team to so to neighb«rring Niger. A {èw days later, the epidemic hit the Zinder region and spread to Maradi, where the research team was in place and waiting, supported by regular resional MSF field teams; the study could be started, and 510 meningitis patients were subsequently recruited for the cohort. The results showed no inferiority of ceftriaxone when compared with oily chloram- phenicol when both are used as short treatments for menin- gococcal meningitis. The authors conclude that ceftriaxone is an equivalent alternative to chloramphenicol for epidemic responses (Nathan et al., 2005). The specificity of this study was
that it was conducted during an epidemic.
The study required a significant amount of technical input from MSF. MSF's logistics potential was a major asset, and the presence of MSF teams across the region and locally, in this case
in Maradi, provided material and technical support fbr research teams. Logistical coordination was another key factor during this intervention, both in material and medical logistics (partic- ularly laboratory ser-vices in the case of meningitis epidemics).
Furthermore, the absence of institutional administrative and diplomatic red tape allowed for reactivity and flexibility that are
not to be found in most state or United Nations bodies. Nor
I Rcrnintlcr: mcningitis lrclt cpidcrnics only last lxrrn a lcw wccks to a crxrplc ol' tnotrths, artrl ovcr livc lrurr<lrcrl paticnts uccrlcrl to bc rccmitc«l li»' thc stu(ly.
did this autonomy undermine interactions with collaborating partners: effective and efficacious collaboration was built with national institutions, particularly the Medical and Sanitary Research Centre of Niger and Nigerien health authorities.
In 2008, both treatment protocols validated by MSF became international standards for meningococcal meningitis outbreaks in the meningitis belt region. The availability of these two drugs means that sporadic cases and epidemic outbreaks can be treated. Both are of significant clinical benefit in the treatment of meningococcal rneningitis.
Vaccines and Vaccination Strategies
Tn.
first trials of anti-meningococcal vaccines were held inI Sudan in 1915, but all efforts to put them into use were in vain until the 1960s. Gotschlich, Goldschneider, and Artenstein, workinS; [br a United StatesArmy research institute, were the {irst
to extract and puriÿ the A and C polysaccharides. Their work demonstrated the immunogenicity of these polysaccharides in man (Gotschlich et al., 1969). A monovalent C polysaccharide vaccine was quickly developed for the United States, where this ser«rgroup predt>minates. 'l-he {irst trials were per{ilrmed
in 1970 in US Ar-y training centers, where regular outbreaks occurred (Artenstein et al., 1970).
This new technology quickly crossed the Atlantic to French- speaking Africa. In 1970-71, Emil Gotschlich and Charles Mérieux collaborated to produce a vaccine providing protection against the meningococcal serogroup A, directly followed by a
study of immune response in cohorts of adults in the United States and children in Dakar (Emil Gotschlich and Michel Rey).
The study demonstrated serogroup A vaccine immunogenicity, although the results suggested that this was lesser than that oI' the C serogroup vaccine. The study also reported that immu-
nogenicity was very poor in infants aged six to thirteen months (Gotschlich, Rey, Tiiau, Sparks, 1972:' Gotschlich, Rey, Etienne, et al., 1972).
The Mérieux Institute launched vaccine production. Lapeys- sonnie, working for the WHO in Alexandria, supported the first controlled trials performed in Egypt in 1972 (Wadhan et al., 1973) and in Sudan in 1973 (Erwa et al., 1973). Immediately following these studies, Charles Mérieux and Lapeyssonnie entrusted the vaccine to Pierre Saliou's team at the tsiology Department of the Muraz Centre in Bobo-Dioulasso. During the outbreaks in Mali and Upper Volta in 1974, Saliou and his team put into place vaccination campaigns to compensate for sulfamide resistance in African strains of Neisseria meningitidis.
'l-he campaigns were deemed a success (Sali<lu, St«reckel, LaI'aye, et al., 1978).
D e s c r i pti o n of I niti al V a c cin ati on Stra tegies
Epidemic control measures \.vere transformed by the arrival of these new anti-meningococcal vaccines (monovalent A and C
and bivalent AC). Lapeyssonnie immediately proposed a guide
to their use at the International Seminar on Immunization,
in Bamako, 1974 (Lapeyssonnie, 1970; Lapeyssonnie, 1974).
Pierre Saliou and Philippe Stoeckel's team then performed several stuclies de{inins the main elements o{'a "circumstantial"
vaccination strateg'y (Saliou et al., 1978; Saliou, Rey, Stoeckel, 1978; Yada et al., 1983).
This strategy is based on epidemiological surveillance at peripheral health centers during the epidemic season. As soon as the first cases are reported, twr-r interventions occur: curative care (treatment of sick patients) to reduce mortality; and the identification of the serogroup involved;with an ensuing circum- stantial vaccination campaign targeting the affected population to stop the spread of the epidemic.
Circumstantial vaccination is a reactive approach. Given that the polysaccharicle vaccine is «rnly immuno5;enic {i«>m tw() years of age, its inclusion as a blanket protective measure in expanded programs of immunization was not feasible. A reactive strategy targets children aged eighteen months through to adults aged
thirty years in the affected region, starting as quickly as possible once the first cases are conflrmed2. The most affected area is the {irst priority, ancl vaccination coverase pft)sressively extends t«>
neighboring areas in expanding concentric circles. The problem is being sensitive enough to react as quickly as possible, but specific enough not to launch unnecessary campaigns because the human and financial inputs for mass vaccination are often
to the detriment of curative care. In other words, the main difficulty resides in the sensitivity and specificity in detection thresholds used.
Several years passed before the first reference study regarding detection thresholds was performed, however. A Centers for
Disease Control and Prevention (CDC)3 team at the beginning of the 1990s analyzed data gathered between 1979 and 1984 in the Burkina Faso epidemiological surveillance system. Because vaccination response depends on the rapidity and the reliability of epidemic detection, the authors proposed an evaluation of the usefulness of a weekly incidence rate using retrospective analysis. 'l-he results suggest acceptable sensitivity and speci- ficity for a threshold of fifteen cases per one hundred thousand inhabitants per week averaged over two weeks for populations of'at least thirty thousand to fifty thclusand, ancl of'five cases per one hundred thousand inhabitants per week for zones neigh- boring epidemic outbreaks. According to the authors, given the rudimentary nature of data collected in Sahel countries'
T Initial snr<lics having shown I)oor sr()ul) A vaccinc irnmrrnogcrricity in infants, carly rccr»rurrcnrlaticlns proposcrl cxclu<ling thctrr liotrr vaccinatiotr carrrpaigns.
3 'l-hc (lfXj, basc<l in Atlanta, in the USÂ, is onc ol'thc thirtccn rnain US I)cpartrncnt ol Hcaltlr arrd Hrurral Scrviccs agcttcit's.
surveillance systems, these measures were acceptable to detect epidemic emergencies. They underlined, however, that further studies were required to examine the appropriateness of these recommendecl thresholds (Mo«>re et al., 1992).
'l'he (lD(l [eam's conclusions quickly became an international standard. In its first Practical, Gtidelin,es for Con,trol, of Epidunic Mcn,in,- gococcal Disease, the IVHO cited the study results, which subse-
quently became official recommendations in epidemic detection and for launching mass vaccination campaigns (WFIO, 1995).
Several retrospective analyses of epidemic responses have progressively called into question the thresholds defined by the CDC team, however. Furthermore, worldwide anti-meningo- coccal vaccine shortages during the 1996 outbreak in Nigeria were decisive in changing the face of vaccination strategies.
MSF Menin giti s V ac cination Experience
MSF interrrened regularly in meningitis belt countries during the 1980s, where teams were confronted by meningitis epidemics. The organization employed the strategies estab- lished by the pioneers of meningitis vaccination in Africa the
preceding decade. Circumstantial vaccination campaigns spreading concentrically from outbreak zones were the rule, such as during the Ugandan epidemic in 1982-83.
At the same time, MSF missions were progressively supported by thc headquarters' medical clepartment and Epicentre. -I-he {irst licld experiences, considerecl in the light ol' impr«>vinu technical analysis, along with capacity-building from centrally documented experiences, led to questions about internationally accepted practices.
MSF missions involving responses to meninsitis epidemics multiplied during the 1990s, mostly in direct collaboration with
national health authorities. Nineteen missions between 1990 and 1999 were formally analyzed by MSF and Epicentre, and these descriptive studies supplied quantitative data about the epidemi- ology of the disease, as well as the effect of responses put in place by national health authorities and NGOs. In 1993 the first two p;uidelines were published (Epicentre, Varaine, 1 993a,b).
The results of these analyses often suggest a weak effect,
if any at all, of vaccination campaigns on overall epidemic progression. For MSF meningitis specialists, it became increas- ingly apparent that preventive measures to control the disease
needed reviewins. Initially, vaccination stratesies datins kom
the 1970s were re-adapted. The "concentric circle" strategy was gradually abandoned in favor of urban agglomeration
outbreak vaccination. These kinds of strategies were based on careful compromises between curative and preventive interven- tions. Simply put, curative care was decentralized with adequate peripheral drug stocks, and vaccination efforts were concen- trated «rn Lhe larsest demouraphic areas hit by the epidemic.
Later, for example in 1996, during the outbreaks in which Nigeria was hardest hit, the need to adapt vaccination strategies became apparent.
Meningitis cases began to be reported in North and East
Nigeria in December 1995. By the beginning of February increasing disease incidence was reported to the national health authorities. The Ministry of Health reinforced the vaccination campaign that had already been launched, and organized an evaluation in affected districts. On February 13, 1996, an MSF team arrived in the country for an exploratory mission to work alongside the government team and the accompanying \MHO and United Nations (lhildren's FLnd ruNf(lEF) statl'to evaluate
the outbreak in the northern and central regions of Nigeria. The mission confirmed a meningitis epidemic outbreak and iden- tified N. meningilidis serogroup A as the causal agent. In four
states, 7 ,400 cases and 1,560 deaths were reported in the first two months of' 1996, a specific mortality rate of 20%. MSF decided to establish a mission to supporL government vaccination activ- ities, curative care, and surveillance-system reinforcement in the three most afÏècted states-a population of fourteen million. The emergency mission grew rapidly and involved the recruitment of
several dozen internati«rnal stalï, the participation ol'all {ive MSI'-
operational centers, and the emergency supply of several tons of medical equipment. From March to May almost three million people were vaccinated and more than thirty thousand cases
treated. A worldwide shortage of vaccine stocks followed.
As the epidemic developed, MSF requested an external evalu- ation of the interventionby the EuropeanAgency lor Development and Health (AEDES).a Their conclusions raised the same ques- tions MSF specialists had been asking previously. Ilevention strat- eeies put into action were compromised by a surueillance system that provided inadequate data in terms of rapidity and reliability:
the mass vaccination campaign's effect was probably weak because
it was introduced too late. Although the authors underlined the Iâct that the results were impressive in terms o[.the number of
people vaccinated and treated, it still appeared painfully obvious that the results obtained were not equal to the significant means employed to achieve them (Farese et al., 1996).
lnternational Health Politics, a New Type of Collaboration Between MSF and the WH)
For the majority of meningitis specialists, including those at the WHO and MSE, the 1996 crisis showed the need to organize a coordinated international response to better confront future epidemics. At the time, WHO reports were asking the same
questions about vaccination s[ratesies as those elucidated in MSF-Epicentre studies. The WHO brought together the world's 4 1-hc AEI)ES is "a consultinra firm, spccializcrl ir-r thc Foo<l, Social anrl Public Hcalth scctoç" arrd a rcgular llpiccntrc collalrorator.
major players in meningitis in Geneva, December 1996. Partici- pants included the CDC, UNICEF, the International Cooper- ation Agency for Preventive Medicine (AMP),i the International Federation of Red Cross and Red Crescent Societies (IFRC), MSR and various scientific specialists. A funding appeal signed by the WHO, UNICEE, the IFRC, and MSF was subsequently launched. The ICG was created in January 1997. Additional technical partners were added to the core organization (the CDC, the Tiopical Medicine Institute of the Military Health
Ser-vice in Marseille,, and the National Public Health Institute in Oslo), as well as vaccine manufacturers.
The first objective of the newly created ICG was to evaluate vaccine needs in meningitis belt countries and compare these with available international resources. Group urembers imrnedi- ately entered int«l discussionswith vaccine manulàcturers to ÉIuar- antee minimum stock levels and costs for epidemic responses.
After estimating epidemic season needs for 1997, a joint inter- national appeal was launched in February for the $6.4 million needed by ICG members. The funds obtained paid for stocks of the first bivalent A C combined vaccines reserves produced by the two manulâcturers at the time: (]laxoSmithKline ((]SK) ancl
Pasteur-Mérieux (later Aventis-Pasteuq then Sanofi Pasteur).
Authorization procedures were created to regulate stock distri- butions. When receiving a request from a Sahel-region country the four members of the ICG guaranteed a consultative answer
within forty-eight, hours, and supply dependins on epidemic risk criteria and proposed vaccination stratesies. The key issues
for ICG members were to evaluate vaccination campaign appro- priateness and to guarantee rational use of supplied vaccines.
In 1997-98, over half of the vaccines supplied to Africa were sourced from the ICG (WHO, 1997).
5 'l-hc ÂMI'is a notr-govcrnrncntal association crcatc<l lry Oharlcs Mérieux an<l f actprcs Mr»rorl in 1!)72. It airns t«r constitrrtc a lclay bc§vccu rcscarch prrrurcss an«l its applicati<»r irr the fic'lrl.